Next generation immunomodulation: targeting specifics of the … · 2017-03-01 · Next generation immunomodulation: targeting specifics of the immune response Emmanuelle Waubant,

Nextgenerationimmunomodulation:targetingspecificsoftheimmune

response

EmmanuelleWaubant,MD,PhDProfessorofNeurology

UCSFFebruary23,2017

Outline

• Possibletargets• Ongoingphase3trials• Ongoingphase2trials• Ongoingphase1trials

Extravasation

astrocytes BRAIN TISSUE

M Y E L I Noligodendrocyte

B cell

Rolling Adhesion

α4 IntegrinVCAM LFA-1

ICAM

B L O O D F L O W

LUMEN OF VENULE

B A S A L L A M I N A

Circulation

Activated T cellProteases (MMPs)

Antigen presenting cell(astrocyte or microglial cell)

Activated microglia/macrophages

IFN-γ, IL-2

Cytokines andchemokines

T CELL REACTIVATION

Activated Macrophage

AutoantibodiesComplement

IL-1, IL-12,chemokines

AXONAL DAMAGE

excess glutamate

GluRProteasesTNF-α

O2•-

NO•

CourtesyofDrs Baranzini andHauser

Treatmentstrategiestargetinginflammation• TargetingS1P1:newgenerationagents• Targetingadhesionmolecules:oralalpha4integrinantagonist(firategrast)• TargetingBcells:CD20,CD19,atacicept• TargetingtheTh17pathway• Inductiontherapy:autologoushematopoieticstemcelltransplant• Inducinganergy withpeptides/TCRpeptides/vaccine• TargetinghumanretrovirusHERV(IgG4againstMRSV-Env)• Targetingmacrophage/microgliaactivation throughthemetabolicsyndrome

andperoxisomeproliferator–activatedreceptorγ (PPARγ)• Dietaryintervention:

– caloricrestriction– lowfatdiet

• Immunemodulationwith:– estriol– vitaminD– mesenchymal stemcells– parasiticbasedapproach– microbiota transplant/probiotic

HormonaltherapyPhase3RCTestrioltrialasanadd-onto

GA

Voskhul 2016

PrimaryEndPoint:

confirmedrelapseatmonth24

Voskhul 2016

Estriolgroup(n=82)

Placebogroup(n=76)

Estriolgroupvsplacebogroup pvalue

At24monthsConfirmed relapse

Annualised relapserate(95%CI) 0·25(0·17–0·37) 0·37(0·25–0·53) 0·63(0·37–1·05)* 0·077

Probability offirstrelapse(95%CI)

33·3%(23·8–45·4)†

42·9%(32·1–55·5)† 0·63%(0·36–1·09)¶ 0·096

RelapseeventAnnualised relapserate(95%CI) 0·32(0·22–0·46) 0·46(0·32–0·65) 0·65(0·39–1·08)* 0·098

Probability offirstrelapseevent(95%CI)

40·5%(30·0–53·0)†

46·9%(35·9–59·3)† 0·70%(0·42–1·17)¶ 0·179

At12monthsConfirmed relapse

Annualised relapserate(95%CI) 0·25(0·16–0·40) 0·48(0·33–0·69) 0·49(0·28–0·88)* 0·016

Probability offirstrelapse(95%CI)

22·8%(15·0–33·7)†

33·1%(23·5–45·2)† 0·58%(0·31–1·10)¶ 0·095

RelapseeventAnnualised relapserate(95%CI) 0·33(0·22–0·50) 0·61(0·44–0·84) 0·52(0·31–0·86)* 0·012

Probability offirstrelapseevent(95%CI)

30·7%(21·7–42·3)†

40·3%(30·0–52·7)† 0·65%(0·37–1·14)¶ 0·131

Voskhul 2016

Ongoingphase3trialsinRRMS

• VitaminD3vs.placebo:– asanadd-ontoGA(VIDAMS)– asanadd-ontoIFNB(SOLAR)– inCIS(Australia)

• Open-labelofALKS8700(monomethyl fumarate,Alkermes Inc.)

• Ofatumumab vs.teriflunomide• Ponesimod vs.teriflunomide• Siponimod

VitaminD:MOA

• Immuneeffects– Increasesexpressionofanti-inflammatorycytokines(IL-4,IL-10,TFGb)

– Inhibitsexpressionofpro-inflammatorycytokines(IL-12,IL-17,IFNg,andTNFa)

– ModulatesThelpercells– Inhibitspro-inflammatoryTh17cells

• Decreasedriskofinfections

VitaminDtoAmeliorateMS(VIDAMS)Trial

PI: Mowry (National MS Society)

SOLARSupplementationofVigantOL®OilversusPlaceboasAdd-oninPatientswithRelapsingRemittingMS

receivingRebif®treatment

• Studydesignmodified:– 229patientsenrolled,vitaminD314,000IU/dvs.placebo(1:1)

– Durationreducedto48weeks– PrimaryendpointchangedtoNoEvidenceofDisease(norelapses,noEDSSchange,nonewenhancinglesions,nonew/enlargingT2lesions)

CourtesyofDr.Mowry

SOLAR:Results

• NomeaningfuldifferenceinratesofNEDA(p=0.91)

• ARR0.28invitaminDgroupversus0.41inplacebogroup(p=0.17)

• VitaminD-treatedgroupwaslesslikelytohavenew/enhancinglesions(1.09versus1.49,p=0.005)

From ECTRIMS 2016 slidesCourtesyofDr.Mowry

Ongoingphase2trials• GNbAC1(IgG4againstMRSV-En,envelopeproteinofhumanretrovirusHERV-W:CHANGE-MS,260patients)

• Amiselimod:S1Preceptormodulator(Biogen)• Bruton tyrosin kinase(BTK)inhibitorM2951vs placebovs dimethylfumarate (EMDSerono):BTKimportantindevelopment/functionofBcellsandmacrophages

• Open-labelofTMP001(tarenflurbil)inRRMS(selectivebetaamyloidlowering:modulateγ secretase andNF-KBpathway)

• LowdoseIL-2vs.placeboinrelapsingMS

Bcelltargeting:MOA

• Anti-CD20• Anti-CD19:inebilizumab• Other:atacicept (recombinantfusionproteinbindingBLyS andAPRILwhichareimportantBcellsignals)

Mancardi, Neurology, 2015

JAMA Neurology, 2015

Event-free survival: 78.4% (90% CI, 60.1%-89.0%) at 3 years.

!

- HSCTstopsrelapses- Nocontrolgroup

CanadianBMTStudy:EDSSandbrainatrophy

!

%changeinbrainvolume

!

%patientswithworseningdisability

Atkins, Freedman et al Lancet, 2016 MSSC-RFCourtesy of Dr Bar-Or

Th1

(IFNγ)

Th17 (IL-17)

29.4 6.9

5.458.4

41.2 1.8

3.153.9

freq

uency(%

)relativ

etobaseline

0

50

100

150

p=0.

012

p=0.

020

p=0.

022

Decreased Th17 (but not Th1) responses following HSCT

Darlington et al, Ann Neurol, 2013Courtesy of Dr Bar-Or

Pre-BMT

Post-BMT

Zou W, Restifo, N. Nat Rev Immunol 10: 248–256 (2010).

TargetingtheTh17pathway:MOA

TargetingtheTh17pathway:phase2• Ustekinumab RCT(againstIL-12/23p40criticalinmaintenanceofTh17cells):noreductioninnewGd+lesionsor#relapses

• Secukinumab (AIN457,againstIL-17A)fullyhumanMABapprovedforpsoriasisgivenIV10mg/kg:RCTproof-of-conceptvs.placeboover24weeks

• CJM112(fullyhumanMABagainstIL-17A,Novartis)givenmonthlySCvs.fingolimod pending(PEPcumulativenumberofnewGd+atmonths4,5and6):360subjects(1:1:1)

• ACEinhibitor:lisinopril asanadjunctivetreatment(NCAT,Dr.Lublin,pending)

Segal2008,Havrdova 2016,Weindl ECTRIMS2016

Secukinumab phase2:PEP

Havrdova 2016

73RRMSrandomized1:1

PEP:-49%cumulative#combineduniqueactivelesions (p=0.087)and-67%cumulative#newGd+(p=0.003) insecukinumab group;

SEP:ARRdecreasedby43%inthesecukinumab group (p>0.05)

Mild/moderate infectionsmorefrequent37%vs 23%

Serumdefensin-2(downstreammarkerofIL-17)

Havrdova 2016

Antigen-specific (tolerizing) strategies:Peptide-based approaches (APL, MBP82-98… b-crystalin)

Route: Oral Tolerance; IV

DNA Vaccines: Dendritic Cell Vaccines

Antigen-Coupled Presentation

Autoreactive T-cell vaccination

T Cell Receptor EngineeringAdoptive Transfer Immunotherapy

Enhancing Regulatory T Cell FunctionEnhancing Regulatory B Cell Function

Anti-Idiotypic NetworksTarget-Competitive Antibody in Tolerization

CourtesyofDr.Bar-Or

Phase1studies

• NeuroVax (enhancesFOXP3+Tregs)TCRpeptidevaccine

• Tolerogenic dendriticcells(TOLERVIT-MS):autologousdendriticcellstreatedwithvitaminD3andmyelinpeptides

• ABT555inrelapsingMSasanadd-ontoGA(AbbVie,axonregenerationanddecreasedmicroglialactivation):antiRMAantibody(repulsiveguidancemolecule)

Trzaska.MolecMedReports1:307,2008CourtesyofDr Cohen

Inaddition,MSCscantrafficfromblood intoinflamedor

injured tissue

Mesenchymal stemcells:MOA

MSC Treatment of Multiple Sclerosis

Reference Indication Participants MSC Source

Cohen submitted RR,SPMS 24 Autologous culture-expandedBMMSCs administeredIV

Connick 2012 SPMS 10 Autologous culture-expandedBMMSCs administeredIV

Karussis 2010 RR, SP,PPMS 15 Autologous culture-expandedBMMSCs administeredIVand IT

Liang2009 PPMS 1 Allogeneicumbilical cordMSCsadministeredIVandITafterCTX

Llufriu 2014 RRMS 9 Autologous culture-expandedBMMSCs administeredIV

Mohyeddin Bonad 2007 Treatment-refractoryMS 10 Autologous culture-expandedBMMSCs administeredIT

Rice 2010 Chronic MS 6 FreshBMcellsenrichedforMSCs

Riordan2009 Treatment-refractoryMS 3 Autologous non-expanded adiposeMSCs

Yamout 2010 SPMS 10 Autologous culture-expandedBMMSCs administeredIT

Phase1TrialofAutologousMSCTransplantationinMS

StudyPopulation 24participantsRRorSP/PRMS(∼12each)EDSS3.0-6.5Activediseaseinprior24monthsAfferentvisualsysteminvolvement

Treatment SingleIVinfusionof1-2x106/kgautologousculture-expandedbone-marrow-derivedMSCs

Follow-up 2monthspre- and6monthspost-treatment

Primaryoutcome Feasibility,andinfusion-relatedsafetyandtolerabilityover1month

CourtesyofDrJeffCohen

DietasaDMT?

• Directeffectsoninflammation

• Impactingcellmetabolismandabilitytodealwithdamage

• Alteringthegutmicrobiota

• Reducingtheoccurrenceofotherillnesses

• OthermechanismsCourtesyofDr.Mowry

ImpactofCalorieRestrictioninEAE

• Restrictingcaloriesorfastingpriortodiseaseinduction:àLowerriskofdiseaseàLesssevereEAEà ReducedproinflammatoryleptinàMayimprovecellenergymetabolism

Piccio 2008, Sanna 2003, Esquifino 2007,Galgani 2010

CourtesyofDr Mowry

Fig.1

Multiple Sclerosis and Related Disorders 2016 9, 80-90DOI: (10.1016/j.msard.2016.07.001) Copyright © 2016 Terms and Conditions

LowfatdietOHSUtrial

Yadav 2016CourtesyofDr Yadav

Fig.2

Multiple Sclerosis and Related Disorders 2016 9, 80-90DOI: (10.1016/j.msard.2016.07.001) Copyright © 2016 Terms and Conditions

Yadav 2016CourtesyofDr Yadav

Day 0 Day 15 Month 3 Month 6

Acute IF phase

§ Control: iv steroids + regular diet § IF: iv steroids +IF

Chronic IF phase All subjects on IF

Clinicalevaluation Blood/serumsample Stoolsample

Calorierestriction(CR)pilotstudyinrelapsingMSpatientsatWashU

• CRisachievedbyIntermittentFasting(IF)

• Sixteenpatientshavebeenenrolled

CourtesyofDrLauraPiccio

ATAC-MSStudyAlteringtheTimingandAmountofCaloriesinMS

Normalcalorieamount

Normalcalories5days/week;25%oftypicalcalories2days/week

Modestcaloriereductioneachday(~78%)

36 eligible people with MS

Courtesy of Dr MowrySponsored by NMSS (Harry Weaver Award)

Phase 1: 8 weeks Phase 2: 40 weeks

Targetingthemetabolicsyndrome

• 50obesepatientswithRRMSandmetabolicsyndrome(hyperinsulinemiaorhyperglycemiaandwaistcircum 94cmormore,dyslipidemiaorHDL,orHBP)

• Openlabel:– 20metformin,– 10pioglitazone,– 20notreatment

• 75-80%onDMTatbaseline,mostlyIFNB• BrainMRIevery6months

Negrotto 2016

Date of download: 1/13/2017 Copyright © 2017 American Medical Association. All rights reserved.

From: Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis

Negrotto et al JAMA Neurol. 2016;73(5):520-528. doi:10.1001/jamaneurol.2015.4807

Disease Activity as Measured by Magnetic Resonance Imaging A, Both metformin hydrochloride and pioglitazone hydrochloride were associated with a significant decrease in the number of new or enlarging T2 lesions in comparison with lesions observed 2 years earlier, and with the control group not receiving metformin or pioglitazone. B, Both metformin and pioglitazone were associated with a significant decrease in the number of gadolinium diethylenetriamine penta-acetic acid (Gd)–enhancing lesions in comparison with lesions observed 2 years earlier, and with the control group not receiving metformin or pioglitazone.

Parasitic-based therapy• Helminths induce a Th2 bias• Trichuris suis ova (TSO) (porcine whipworm) in 15

subjects with early RRMS• PEP:

– 1) safety/tolerability of TSO – 2) changes in #Gd+ on monthly brain MRI

Courtesy of Dr. Fleming

MRI Results

Courtesy of Dr. Fleming

Conclusions

• Diversetargetsandstrategiestoaddressinflammation

• Mostnoveltherapeuticstrategiesareinphase1and2trials